Nintedanib* Receives Positive CHMP Opinion in European Union for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

BRACKNELL, England, November 24, 2014 /PRNewswire/ --

• Recommendation supported by data from two identical Phase III trials involving more than 1,000 patients^[1]
• Data showed that nintedanib^[*]slowed disease progression by reducing annual decline in lung function by approximately 50%^[1]
• Nintedanib^[*]also significantly reduced the risk of adjudicated acute exacerbations^[**] by 68% (p=0.001)^[2]

Boehringer Ingelheim today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for nintedanib^[*] (suggested brand name OFEV®) for the treatment of patients with idiopathic pulmonary fibrosis (IPF).

Results from the Phase III INPULSIS® trials, published in the New England Journal of Medicine in May 2014, showed that nintedanib^[*] significantly slowed disease progression in patients with IPF.^[1] The opinion follows the recent Food and Drug Administration (FDA) approval of nintedanib^[*] for the treatment of IPF.

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* Nintedanib is currently being assessed by the European Medicines Agency (EMA) and other regulatory organisations worldwide

** 'Adjudicated exacerbations' was a pre-specified sensitivity analysis in the pooled data set. Time to first Investigator-reported confirmed and suspected acute exacerbation was a secondary endpoint which was met in the Phase II TOMORROW and INPULSIS®-2 but not in INPULSIS®-1

"This decision is very encouraging as patients with IPF currently have very limited treatment options," said INPULSIS® study investigator Professor Luca Richeldi, Professor of Respiratory Medicine, Chair of Interstitial Lung Disease at the University of Southampton, United Kingdom. "For the first time we have a drug that has consistently met the primary endpoint in two large Phase III trials, confirming the results of the Phase II trial."

Idiopathic pulmonary fibrosis (IPF) is a progressive and severely debilitating lung disease with a high mortality rate.^[3] It causes progressive scarring of the lungs, resulting in continual and irreversible deterioration in lung function and difficulty breathing.^[4] In patients with IPF, lung function loss is measured by a decline in a patient's forced vital capacity (FVC), the maximum volume of breath that can be exhaled. The average IPF patient has lung volume loss of between 150-200mL per year, compared to a normal adult lung volume decline of approximately 50ml per year.^[5];[6]

Dr Charles de Wet, UK Medical Director at Boehringer Ingelheim, commented, "Boehringer Ingelheim welcomes the decision by the CHMP to grant nintedanib a positive opinion. IPF is a highly debilitating disease for patients and there are currently only limited treatment options that are able to slow disease progression. We hope that we are able to make nintedanib available to these patients in the EU soon."

The CHMP's positive opinion is based on pivotal data from the replicate Phase III INPULSIS® trials involving 1,066 patients from 24 countries.^[1]

INPULSIS® results showed that nintedanib^[*] slowed disease progression by reducing the annual rate of decline in lung function by approximately 50% in IPF patients. This included patients with early disease (forced vital capacity (FVC) >90% predicted), limited radiographic fibrosis (no honeycombing) on high resolution computed tomography (HRCT) and those with emphysema.^[1] Nintedanib^[*] also significantly reduced the risk of adjudicated acute exacerbations by 68%.†^[1];[2] This is important given that approximately half of patients hospitalised for an acute IPF exacerbation die during hospitalisation.^[7]

The most frequent adverse event in the nintedanib^[*] groups was diarrhoea, reported in 62% of patients vs. 19% in the placebo arm (INPULSIS®-1) and 63% vs. 18% (INPULSIS®-2). Less than 5% of those who experienced diarrhoea in the nintedanib* groups of INPULSIS®-1 and INPULSIS®-2 discontinued treatment due to this event.^[1]

Nintedanib^[*] in IPF has been granted accelerated assessment by the EMA. It is the first targeted treatment for IPF that has consistently demonstrated the ability to slow disease progression by significantly reducing decline in lung function (p<0.001) with a manageable side effect profile.^[1]

Notes to Editor 

About the INPULSIS^® trials

INPULSIS^®‐1 and ‐2 are two global Phase III trials evaluating the efficacy and safety of nintedanib* in the treatment of idiopathic pulmonary fibrosis (IPF).^[8]

The double blind, randomised and placebo-controlled trials evaluated the effect of oral nintedanib^[*], 150 mg twice daily, on the annual rate of decline in forced vital capacity (FVC), in patients with IPF over 52 weeks. The trials had an identical design, matched dosing, inclusion criteria, and endpoints.^[8]

The primary endpoint was the annual rate of decline in FVC (expressed in mL over 52 weeks). Key secondary endpoints were: change from baseline in health-related quality of life, as assessed by the St. George's Respiratory Questionnaire (SGRQ); time to first acute exacerbation (number of days). Other secondary endpoints included change from baseline in FVC, overall survival, respiratory mortality, on-treatment survival.^[8]

Patients included in the trials were at least 40 years of age, diagnosed with IPF within five years prior to enrolment, based on the most recent American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) IPF guidelines for diagnosis and management.^[8]

More information can be found on clinicaltrials.gov (identifiers NCT01335464 and NCT01335477).

About nintedanib^[*]

Nintedanib^[*] is an investigational small molecule tyrosine kinase inhibitor (TKI) in development by Boehringer Ingelheim for idiopathic pulmonary fibrosis (IPF).^[9] It has been granted orphan drug designation in the EU,

United States and Japan.^[10]-[12]

Nintedanib^[*] targets growth factor receptors, which have been shown to be potentially involved in the pathenogenesis of idiopathic pulmonary fibrosis, most importantly the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet‐derived growth factor receptor (PDGFR).^[13]

Nintedanib^[*] is also in clinical development as a treatment option for cancer, including non‐small cell lung cancer and ovarian cancer, and in earlier stages of development for renal cell cancer, colorectal cancer and hepatocellular cancer.^[14]

About idiopathic pulmonary fibrosis 

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, severely debilitating and ultimately fatal lung disease for which there are limited treatment options.^[3] IPF is characterised by inflammation and scarring of lung tissue and loss of lung function over time.^[3];[15] This build-up of scar tissue is called 'fibrosis.' As the lung tissue becomes thick and stiff with scarring, the

lungs lose their ability to take in oxygen from the air and transfer it to the bloodstream.^[16] As a result, individuals with IPF experience shortness of breath, cough and often have difficulty participating in everyday physical activities.^[17]

Every year in the UK, more than 5,000 people are diagnosed with the disease,^[18] with a median survival time of three years from diagnosis.^[19]

For more information please visit http://www.boehringer-ingelheim.co.uk

About Boehringer Ingelheim 

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative "Making More Health" and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2013, Boehringer Ingelheim achieved net sales of about €14.1 billion. R&D expenditure corresponds to 19.5% of its net sales.

Reference List

(1) Richeldi L, Du Bois R, Raghu G et al. Efficacy and Safety of nintedanib in Idiopathic Pulmonary Fibrosis. N Engl J Med 2014; published online 18 May:DOI: 10.1056/NEJMoa1402584.

(2) Richeldi L, Du Bois R, Raghu G et al. Efficacy and Safety of nintedanib in Idiopathic Pulmonary Fibrosis - Supplementary Appendix. N Engl J Med 2014; published online 18 May:DOI: 10.1056/NEJMoa1402584.

(3) Raghu G, Collard H, Egan J. An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med 2011; 183:788-824.

(4) Collard H, Moore B, Flaherty K et al. Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2007;636-643.

(5) Ley B, Collard H, King T. Clinical Course and Prediction of Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2011; 183:431-440.

(6) Association for Respiratory Technology and Physiology. Predicted FVC for Men (18 to 60). 2014. Available at: http://www.alpha1awareness.org.uk/wp-content/uploads/2012/06/Predicted-FEV1-FVD-Men.pdf. Last accessed: November 2014.

(7) Song J, Hong-SB, Koh Y et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011; 34:356-363.

(8) Richeldi L, Cottin V, Flaherty L et al. Design Of The INPULSIS Trials: Two Phase 3 Trials Of Nintedanib In Patients With Idiopathic Pulmonary Fibrosis. Respir Med 2014; 108:1023-1030.

(9) Richeldi L, Costabel U, Selman M. Efficacy of a Tyrosine Kinase inhibitor in Idiopathic Pulmonary Fibrosis. N Engl J Med 2011; 365:1079-1087.

(10) Food and Drug Administration. Orphan Drug Designations and Approvals. 2011. Available at: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=344511. Last accessed: November 2014.

(11) European Medicines Agency. Medicines for Rare Diseases. 2014. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000034.jsp&mid=WC0b01ac058002d4eb. Last accessed: November 2014.

(12) Ministry of Health, Labour and Welfare. List of products designated as orphan drugs for rare diseases. 2011. Available at: http://www.nibio.go.jp/shinko/orphan/english/pdf/h2412kisyoiyaku-hyo1.pdf. Last accessed: November 2014.

(13) Hilberg F, Roth G, Krssak M et al. BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor BLockade and Good Antitumor Efficacy. Cancer Res 2008; 68:4774-4782.

(14) Boehringer Ingelheim. Nintedanib (BIBF 1120) fact sheet. 2013. Available at: http://us.boehringer-ingelheim.com/content/dam/internet/opu/us_EN/documents/Media_Press_Releases/2013/BI-Nintedanib-Fact-Sheet-2013.pdf. Last accessed: November 2014.

(15) Bergeron A, Soler P, Kambouchner P. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-b and IL-10. Eur Respir J 2003; 22:69-76.

(16) British Lung Foundation. Information sheet: Idiopathic pulmonary fibrosis and other types of interstitial lung disease. Available at: http://www.blf.org.uk/Conditions/Detail/IPF. Last accessed: November 2014.

(17) Pulmonary Fibrosis Foundation. Symptoms of Pulmonary Fibrosis. 2013. Available at: http://www.pulmonaryfibrosis.org/symptoms. Last accessed: November 2014.

(18) Navaratnam V. The rising incidence of idiopathic pulmonary fibrosis in the UK. Thorax 2011; 66:462-467.

(19) National Institute of Health and Care Excellence (NICE). Diagnosis and management of suspected idiopathic pulmonary fibrosis. 2013. Available at: http://www.nice.org.uk/nicemedia/live/14183/64119/64119.pdf. Last accessed: November 2014.

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